Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy

ABSTRACT

Provided herein are methods for treating or preventing a cancer, comprising administering an effective amount of a Dihydropyrazino-Pyrazine Compound and an effective amount of an androgen receptor antagonist to a patient having a cancer.

This application is a continuation of U.S. application Ser. No.14/254,017, filed Apr. 16, 2014, currently allowed, which claims thebenefit of U.S. Provisional Application No. 61/813,038, filed Apr. 17,2013 and U.S. Provisional Application No. 61/815,509, filed Apr. 24,2013, the entire contents of which are incorporated herein by reference.

1. FIELD

Provided herein are methods for treating or preventing a cancer,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound and an effective amount of an androgenreceptor antagonist to a patient having a cancer.

2. BACKGROUND

The connection between abnormal protein phosphorylation and the cause orconsequence of diseases has been known for over 20 years. Accordingly,protein kinases have become a very important group of drug targets. SeeCohen, Nature, 1:309-315 (2002). Various protein kinase inhibitors havebeen used clinically in the treatment of a wide variety of diseases,such as cancer and chronic inflammatory diseases, including diabetes andstroke. See Cohen, Eur. J. Biochem., 268:5001-5010 (2001), ProteinKinase Inhibitors for the Treatment of Disease: The Promise and theProblems, Handbook of Experimental Pharmacology, Springer BerlinHeidelberg, 167 (2005).

The protein kinases are a large and diverse family of enzymes thatcatalyze protein phosphorylation and play a critical role in cellularsignaling. Protein kinases may exert positive or negative regulatoryeffects, depending upon their target protein. Protein kinases areinvolved in specific signaling pathways which regulate cell functionssuch as, but not limited to, metabolism, cell cycle progression, celladhesion, vascular function, apoptosis, and angiogenesis. Malfunctionsof cellular signaling have been associated with many diseases, the mostcharacterized of which include cancer and diabetes. The regulation ofsignal transduction by cytokines and the association of signal moleculeswith protooncogenes and tumor suppressor genes have been welldocumented. Similarly, the connection between diabetes and relatedconditions, and deregulated levels of protein kinases, has beendemonstrated. See e.g., Sridhar et al. Pharmaceutical Research, 17 (11):1345-1353 (2000). Viral infections and the conditions related theretohave also been associated with the regulation of protein kinases. Parket al. Cell 101 (7): 777-787 (2000).

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

Protein kinases have become attractive targets for the treatment ofcancers. Fabbro et al., Pharmacology & Therapeutics 93:79-98 (2002). Ithas been proposed that the involvement of protein kinases in thedevelopment of human malignancies may occur by: (1) genomicrearrangements (e.g., BCR-ABL in chronic myelogenous leukemia), (2)mutations leading to constitutively active kinase activity, such asacute myelogenous leukemia and gastrointestinal tumors, (3) deregulationof kinase activity by activation of oncogenes or loss of tumorsuppressor functions, such as in cancers with oncogenic RAS, (4)deregulation of kinase activity by over-expression, as in the case ofEGFR and (5) ectopic expression of growth factors that can contribute tothe development and maintenance of the neoplastic phenotype. Fabbro etal., Pharmacology & Therapeutics 93:79-98 (2002).

The elucidation of the intricacy of protein kinase pathways and thecomplexity of the relationship and interaction among and between thevarious protein kinases and kinase pathways highlights the importance ofdeveloping pharmaceutical agents capable of acting as protein kinasemodulators, regulators or inhibitors that have beneficial activity onmultiple kinases or multiple kinase pathways. Accordingly, there remainsa need for new kinase modulators.

The protein named mTOR (mammalian target of rapamycin), which is alsocalled FRAP, RAFTI or RAPTI), is a 2549-amino acid Ser/Thr proteinkinase, that has been shown to be one of the most critical proteins inthe mTOR/PI3K/Akt pathway that regulates cell growth and proliferation.Georgakis and Younes Expert Rev. Anticancer Ther. 6(1):131-140 (2006).mTOR exists within two complexes, mTORC1 and mTORC2. While mTORC1 issensitive to rapamycin analogs (such as temsirolimus or everolimus),mTORC2 is largely rapamycin-insensitive. Notably, rapamycin is not a TORkinase inhibitor. Several mTOR inhibitors have been or are beingevaluated in clinical trials for the treatment of cancer. Temsirolimuswas approved for use in renal cell carcinoma in 2007 and sirolimus wasapproved in 1999 for the prophylaxis of renal transplant rejection.Everolimus was approved in 2009 for renal cell carcinoma patients thathave progressed on vascular endothelial growth factor receptorinhibitors, in 2010 for subependymal giant cell astrocytoma (SEGA)associated with tuberous sclerosis (TS) in patients who require therapybut are not candidates for surgical resection, and in 2011 forprogressive neuroendocrine tumors of pancreatic origin (PNET) inpatients with unresectable, locally advanced or metastatic disease.There remains a need for TOR kinase inhibitors that inhibit both mTORC1and mTORC2 complexes.

DNA-dependent protein kinase (DNA-PK) is a serine/threonine kinaseinvolved in the repair of DNA double strand breaks (DSBs). DSBs areconsidered to be the most lethal DNA lesion and occur endogenously or inresponse to ionizing radiation and chemotherapeutics (for review seeJackson, S. P., Bartek, J. The DNA-damage response in human biology anddisease. Nature Rev 2009; 461:1071-1078). If left unrepaired, DSBs willlead to cell cycle arrest and/or cell death (Hoeijmakers, J. H. J.Genome maintenance mechanisms for preventing cancer. Nature 2001; 411:366-374; van Gent, D. C., Hoeijmakers, J. H., Kanaar, R. Chromosomalstability and the DNA double-stranded break connection. Nat Rev Genet2001; 2: 196-206). In response to the insult, cells have developedcomplex mechanisms to repair such breaks and these mechanisms may formthe basis of therapeutic resistance. There are two major pathways usedto repair DSBs, non-homologous end joining (NHEJ) and homologousrecombination (HR). NHEJ brings broken ends of the DNA together andrejoins them without reference to a second template (Collis, S. J.,DeWeese, T. L., Jeggo P. A., Parker, A. R. The life and death of DNA-PK.Oncogene 2005; 24: 949-961). In contrast, HR is dependent on theproximity of the sister chromatid which provides a template to mediatefaithful repair (Takata, M., Sasaki, M. S., Sonoda, E., Morrison, C.,Hashimoto, M., Utsumi, H., et al. Homologous recombination andnon-homologous end-joining pathways of DNA double-strand break repairhave overlapping roles in the maintenance of chromosomal integrity invertebrate cells. EMBO J 1998; 17: 5497-5508; Haber, J. E. Partners andpathways repairing a double-strand break. Trends Genet 2000; 16:259-264). NHEJ repairs the majority of DSBs. In NHEJ, DSBs arerecognized by the Ku protein that binds and then activates the catalyticsubunit of DNA-PK. This leads to recruitment and activation ofend-processing enzymes, polymerases and DNA ligase IV (Collis, S. J.,DeWeese, T. L., Jeggo P. A., Parker, A. R. The life and death of DNA-PK.Oncogene 2005; 24: 949-961). NHEJ is primarily controlled by DNA-PK andthus inhibition of DNA-PK is an attractive approach to modulating therepair response to exogenously induced DSBs. Cells deficient incomponents of the NHEJ pathway are defective in DSB repair and highlysensitive to ionizing radiation and topoisomerase poisons (reviewed bySmith, G. C. M., Jackson, S. P. The DNA-dependent protein kinase. GenesDev 1999; 13: 916-934; Jeggo, P. A., Caldecott, K., Pidsley, S., Banks,G. R. Sensitivity of Chinese hamster ovary mutants defective in DNAdouble strand break repair to topoisomerase II inhibitors. Cancer Res1989; 49: 7057-7063). A DNA-PK inhibitor has been reported to have thesame effect of sensitizing cancer cells to therapeutically induced DSBs(Smith, G. C. M., Jackson, S. P. The DNA-dependent protein kinase. GenesDev 1999; 13: 916-934).

Citation or identification of any reference in Section 2 of thisapplication is not to be construed as an admission that the reference isprior art to the present application.

3. SUMMARY

Provided herein are methods for treating or preventing a cancer,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound and an effective amount of an androgenreceptor antagonist to a patient having a cancer.

In certain embodiments, provided herein are methods for achieving aResponse Evaluation Criteria in Solid Tumors (for example, RECIST 1.1)of complete response, partial response or stable disease in a patienthaving a solid tumor, comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist to said patient. In certain embodiments, providedherein are methods for achieving a Prostate Cancer Working Group 2(PCWG2) Criteria of complete response, partial response or stabledisease in a patient having prostate cancer, comprising administering aneffective amount of a Dihydropyrazino-Pyrazine Compound in combinationwith an androgen receptor antagonist to said patient.

In certain embodiments, provided herein are methods for increasingsurvival without tumor progression of a patient having a cancer,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to said patient.

In certain embodiments, the Dihydropyrazino-Pyrazine Compound is acompound as described herein. In certain embodiments, the androgenreceptor antagonist is MDV3100.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts Compound 2 monotherapy and MDV3100 monotherapy in anETS-positive prostate cancer xenograft model.

FIG. 2 depicts Compound 2 monotherapy, MDV3100 monotherapy and Compound2+MDV3100 combination therapy in an ETS-positive prostate cancerxenograft model.

FIGS. 3A-3E depict Compound 2 and MDV3100 combination treatment synergyin apoptosis induction. In FIG. 3A Caspase activity of single treatmentwith Compound 2 or MDV3100 of the LNCaP cell line (ETS+, Androgendependent) is shown. FIGS. 3B, C and D show 3 experiments measuring thecaspase activity of combined treatment with Compound 2 and MDV3100:Compound 2 treatment alone (triangles), the expected additive effect ofCompound 2 with 30, 10, 3.3 and 1.1 μM MDV3100 (+), and the actualcombination effect of Compound 2 and MDV3100 treatment (circles), asmeasured by caspase induction. FIG. 3E shows an experiment measuring thecaspase activity of treatment with Compound 2 and MDV3100 of the VCaPcell line (ETS+, Androgen dependent): Compound 2 treatment alone(triangles), the expected additive effect of Compound 2 with 30, 10, 3.3and 1.1 μM MDV3100 (+), and the actual combination effect of Compound 2and MDV3100 treatment (circles), as measured by caspase induction.

FIG. 4 depicts Compound 2 monotherapy, MDV3100 monotherapy and Compound2+MDV3100 combination therapy in a LNCap-HR prostate cancer xenograftmodel.

5. DETAILED DESCRIPTION 5.1 Definitions

An “alkyl” group is a saturated, partially saturated, or unsaturatedstraight chain or branched non-cyclic hydrocarbon having from 1 to 10carbon atoms, typically from 1 to 8 carbons or, in some embodiments,from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkylgroups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and-n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃)and —CH₂C≡C(CH₂CH₃), among others. An alkyl group can be substituted orunsubstituted. In certain embodiments, when the alkyl groups describedherein are said to be “substituted,” they may be substituted with anysubstituent or substituents as those found in the exemplary compoundsand embodiments disclosed herein, as well as halogen (chloro, iodo,bromo, or fluoro); hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino;carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine;guanidine; enamine; aminocarbonyl; acylamino; phosphonato; phosphine;thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester;urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoxyamine;N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate;isothiocyanate; cyanate; thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl.

An “alkenyl” group is a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms, typically from 2 to 8carbon atoms, and including at least one carbon-carbon double bond.Representative straight chain and branched (C₂-C₈)alkenyls include-vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl,-2-pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl,-2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,-1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2-octenyl,-3-octenyl and the like. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. An alkenylgroup can be unsubstituted or substituted.

A “cycloalkyl” group is a saturated, or partially saturated cyclic alkylgroup of from 3 to 10 carbon atoms having a single cyclic ring ormultiple condensed or bridged rings which can be optionally substitutedwith from 1 to 3 alkyl groups. In some embodiments, the cycloalkyl grouphas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structuressuch as adamantyl and the like. Examples of unsaturated cycloalkylgroups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanone and the like.

An “aryl” group is an aromatic carbocyclic group of from 6 to 14 carbonatoms having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl or anthryl). In some embodiments, aryl groups contain6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms inthe ring portions of the groups. Particular aryls include phenyl,biphenyl, naphthyl and the like. An aryl group can be substituted orunsubstituted. The phrase “aryl groups” also includes groups containingfused rings, such as fused aromatic-aliphatic ring systems (e.g.,indanyl, tetrahydronaphthyl, and the like).

A “heteroaryl” group is an aryl ring system having one to fourheteroatoms as ring atoms in a heteroaromatic ring system, wherein theremainder of the atoms are carbon atoms. In some embodiments, heteroarylgroups contain 5 to 6 ring atoms, and in others from 6 to 9 or even 6 to10 atoms in the ring portions of the groups. Suitable heteroatomsinclude oxygen, sulfur and nitrogen. In certain embodiments, theheteroaryl ring system is monocyclic or bicyclic. Non-limiting examplesinclude but are not limited to, groups such as pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,benzothiophenyl, furanyl, benzofuranyl (for example,isobenzofuran-1,3-diimine), indolyl, azaindolyl (for example,pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl(for example, 1H-benzo[d]imidazolyl), imidazopyridyl (for example,azabenzimidazolyl, 3H-imidazo[4,5-b]pyridyl or1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups.

A “heterocyclyl” is an aromatic (also referred to as heteroaryl) ornon-aromatic cycloalkyl in which one to four of the ring carbon atomsare independently replaced with a heteroatom from the group consistingof O, S and N. In some embodiments, heterocyclyl groups include 3 to 10ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8ring members. Heterocyclyls can also be bonded to other groups at anyring atom (i.e., at any carbon atom or heteroatom of the heterocyclicring). A heterocyclylalkyl group can be substituted or unsubstituted.Heterocyclyl groups encompass unsaturated, partially saturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase heterocyclyl includes fused ringspecies, including those comprising fused aromatic and non-aromaticgroups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. Representative examples of aheterocyclyl group include, but are not limited to, aziridinyl,azetidinyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl,isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydropyranyl (for example,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl;for example, 1H-imidazo[4,5-b]pyridyl, or1H-imidazo[4,5-b]pyridin-2(3H)-onyl), triazolopyridyl, isoxazolopyridyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed below.

A “cycloalkylalkyl” group is a radical of the formula:-alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, thecycloalkyl, or both the alkyl and the cycloalkyl portions of the group.Representative cycloalkylalkyl groups include but are not limited tocyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl,and cyclohexylpropyl. Representative substituted cycloalkylalkyl groupsmay be mono-substituted or substituted more than once.

An “aralkyl” group is a radical of the formula: -alkyl-aryl, whereinalkyl and aryl are defined above. Substituted aralkyl groups may besubstituted at the alkyl, the aryl, or both the alkyl and the arylportions of the group. Representative aralkyl groups include but are notlimited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkylgroups such as 4-ethyl-indanyl.

A “heterocyclylalkyl” group is a radical of the formula:-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.Substituted heterocyclylalkyl groups may be substituted at the alkyl,the heterocyclyl, or both the alkyl and the heterocyclyl portions of thegroup. Representative heterocylylalkyl groups include but are notlimited to 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl,furan-3-yl methyl, pyrdine-3-yl methyl,(tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yl)ethyl,tetrahydrofuran-2-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-ylpropyl.

A “halogen” is chloro, iodo, bromo, or fluoro.

A “hydroxyalkyl” group is an alkyl group as described above substitutedwith one or more hydroxy groups.

An “alkoxy” group is —O-(alkyl), wherein alkyl is defined above.

An “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is definedabove.

An “amine” group is a radical of the formula: —NH₂.

A “hydroxyl amine” group is a radical of the formula: —N(R^(#))OH or—NHOH, wherein R^(#) is a substituted or unsubstituted alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

An “alkoxyamine” group is a radical of the formula: —N(R^(#))O-alkyl or—NHO-alkyl, wherein R^(#) is as defined above.

An “aralkoxyamine” group is a radical of the formula: —N(R^(#))O-aryl or—NHO-aryl, wherein R^(#) is as defined above.

An “alkylamine” group is a radical of the formula: —NH-alkyl or—N(alkyl)₂, wherein each alkyl is independently as defined above.

An “aminocarbonyl” group is a radical of the formula: —C(═O)N(R^(#))₂,—C(═O)NH(R^(#)) or —C(═O)NH₂, wherein each R^(#) is as defined above.

An “acylamino” group is a radical of the formula: —NHC(═O)(R^(#)) or—N(alkyl)C(═O)(R^(#)), wherein each alkyl and R^(#) are independently asdefined above.

An “O(alkyl)aminocarbonyl” group is a radical of the formula:—O(alkyl)C(═O)N(R^(#))₂, —O(alkyl)C(═O)NH(R^(#)) or —O(alkyl)C(═O)NH₂,wherein each R^(#) is independently as defined above.

An “N-oxide” group is a radical of the formula: —N⁺—O⁻.

A “carboxy” group is a radical of the formula: —C(═O)OH.

A “ketone” group is a radical of the formula: —C(═O)(R^(#)), whereinR^(#) is as defined above.

An “aldehyde” group is a radical of the formula: —CH(═O).

An “ester” group is a radical of the formula: —C(═O)O(R^(#)) or—OC(═O)(R^(#)), wherein R^(#) is as defined above.

A “urea” group is a radical of the formula: —N(alkyl)C(═O)N(R^(#))₂,—N(alkyl)C(═O)NH(R^(#)), —N(alkyl)C(═O)NH₂, —NHC(═O)N(R^(#))₂,—NHC(═O)NH(R^(#)), or —NHC(═O)NH₂ ^(#), wherein each alkyl and R^(#) areindependently as defined above.

An “imine” group is a radical of the formula: —N═C(R^(#))₂ or—C(R^(#))═N(R^(#)), wherein each R^(#) is independently as definedabove.

An “imide” group is a radical of the formula: —C(═O)N(R#)C(═O)(R^(#)) or—N((C═O)(R^(#)))₂, wherein each R^(#) is independently as defined above.

A “urethane” group is a radical of the formula: —OC(═O)N(R^(#))₂,—OC(═O)NH(R^(#)), —N(R^(#))C(═O)O(R^(#)), or —NHC(═O)O(R^(#)), whereineach R^(#) is independently as defined above.

An “amidine” group is a radical of the formula: —C(═N(R^(#)))N(R^(#))₂,—C(═N(R^(#)))NH(R^(#)), —C(═N(R^(#)))NH₂, —C(═NH)N(R^(#))₂,—C(═NH)NH(R^(#)), —C(═NH)NH₂, —N═C(R^(#))N(R^(#))₂,—N═C(R^(#))NH(R^(#)), —N═C(R^(#))NH₂, —N(R^(#))C(R^(#))═N(R^(#)),—NHC(R^(#))═N(R^(#)), —N(R^(#))C(R^(#))═NH, or —NHC(R^(#))═NH, whereineach R^(#) is independently as defined above.

A “guanidine” group is a radical of the formula:—N(R^(#))C(═N(R^(#)))N(R^(#))₂, —NHC(═N(R^(#)))N(R^(#))₂,—N(R^(#))C(═NH)N(R^(#))₂, —N(R^(#))C(═N(R^(#)))NH(R^(#)),—N(R^(#))C(═N(R^(#)))NH₂, —NHC(═NH)N(R^(#))₂, —NHC(═N(R^(#)))NH(R^(#)),—NHC(═N(R^(#)))NH₂, —NHC(═NH)NH(R^(#)), —NHC(═NH)NH₂, —N═C(N(R^(#))₂)₂,—N═C(NH(R^(#)))₂, or —N═C(NH₂)₂, wherein each R^(#) is independently asdefined above.

A “enamine” group is a radical of the formula:—N(R^(#))C(R^(#))═C(R^(#))₂, —NHC(R^(#))═C(R^(#))₂,—C(N(R^(#))₂)═C(R^(#))₂, —C(NH(R^(#)))═C(R^(#))₂, —C(NH₂)═C(R^(#))₂,—C(R^(#))═C(R^(#))(N(R^(#))₂), —C(R^(#))═C(R^(#))(NH(R^(#))) or—C(R^(#))═C(R^(#))(NH₂), wherein each R^(#) is independently as definedabove.

An “oxime” group is a radical of the formula: —C(═NO(R^(#)))(R^(#)),—C(═NOH)(R^(#)), —CH(═NO(R^(#))), or —CH(═NOH), wherein each R^(#) isindependently as defined above.

A “hydrazide” group is a radical of the formula:—C(═O)N(R^(#))N(R^(#))₂, —C(═O)NHN(R^(#))₂, —C(═O)N(R^(#))NH(R^(#)),—C(═O)N(R^(#))NH₂, —C(═O)NHNH(R^(#))₂, or —C(═O)NHNH₂, wherein eachR^(#) is independently as defined above.

A “hydrazine” group is a radical of the formula: —N(R^(#))N(R^(#))₂,—NHN(R^(#))₂, —N(R^(#))NH(R^(#)), —N(R^(#))NH₂, —NHNH(R^(#))₂, or—NHNH₂, wherein each R^(#) is independently as defined above.

A “hydrazone” group is a radical of the formula:—C(═N—N(R^(#))₂)(R^(#))₂, —C(═N—NH(R^(#)))(R^(#))₂, —C(═N—NH₂)(R^(#))₂,—N(R^(#))(N═C(R^(#))₂), or —NH(N═C(R^(#))₂), wherein each R^(#) isindependently as defined above.

An “azide” group is a radical of the formula: —N₃.

An “isocyanate” group is a radical of the formula: —N═C═O.

An “isothiocyanate” group is a radical of the formula: —N═C═S.

A “cyanate” group is a radical of the formula: —OCN.

A “thiocyanate” group is a radical of the formula: —SCN.

A “thioether” group is a radical of the formula; —S(R^(#)), whereinR^(#) is as defined above.

A “thiocarbonyl” group is a radical of the formula: —C(═S)(R^(#)),wherein R^(#) is as defined above.

A “sulfinyl” group is a radical of the formula: —S(═O)(R^(#)), whereinR^(#) is as defined above.

A “sulfone” group is a radical of the formula: —S(═O)₂(R^(#)), whereinR^(#) is as defined above.

A “sulfonylamino” group is a radical of the formula: —NHSO₂(R^(#)) or—N(alkyl)SO₂(R^(#)), wherein each alkyl and R^(#) are defined above.

A “sulfonamide” group is a radical of the formula: —S(═O)₂N(R^(#))₂, or—S(═O)₂NH(R^(#)), or —S(═O)₂NH₂, wherein each R^(#) is independently asdefined above.

A “phosphonate” group is a radical of the formula: —P(═O)(O(R^(#)))₂,—P(═O)(OH)₂, —OP(═O)(O(R^(#)))(R^(#)), or —OP(═O)(OH)(R^(#)), whereineach R^(#) is independently as defined above.

A “phosphine” group is a radical of the formula: —P(R^(#))₂, whereineach R^(#) is independently as defined above.

When the groups described herein, with the exception of alkyl group aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl;alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol;thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl;acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone;sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide;hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate;oxygen (═O); B(OH)₂, O(alkyl)aminocarbonyl; cycloalkyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may bemonocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl,piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fusedor non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl,pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl,quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy;aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of theDihydropyrazino-Pyrazine Compounds include, but are not limited tometallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Examples of specific salts thus includehydrochloride and mesylate salts. Others are well-known in the art, seefor example, Remington's Pharmaceutical Sciences, 18^(th) eds., MackPublishing, Easton Pa. (1990) or Remington: The Science and Practice ofPharmacy, 19^(th) eds., Mack Publishing, Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “clathrate”means a Dihydropyrazino-Pyrazine Compound, or a salt thereof, in theform of a crystal lattice that contains spaces (e.g., channels) thathave a guest molecule (e.g., a solvent or water) trapped within or acrystal lattice wherein a Dihydropyrazino-Pyrazine Compound is a guestmolecule.

As used herein and unless otherwise indicated, the term “solvate” meansa Dihydropyrazino-Pyrazine Compound, or a salt thereof, that furtherincludes a stoichiometric or non-stoichiometric amount of a solventbound by non-covalent intermolecular forces. In one embodiment, thesolvate is a hydrate.

As used herein and unless otherwise indicated, the term “hydrate” meansa Dihydropyrazino-Pyrazine Compound, or a salt thereof, that furtherincludes a stoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “prodrug” meansa Dihydropyrazino-Pyrazine Compound derivative that can hydrolyze,oxidize, or otherwise react under biological conditions (in vitro or invivo) to provide an active compound, particularly aDihydropyrazino-Pyrazine Compound. Examples of prodrugs include, but arenot limited to, derivatives and metabolites of aDihydropyrazino-Pyrazine Compound that include biohydrolyzable moietiessuch as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. In certain embodiments, prodrugs ofcompounds with carboxyl functional groups are the lower alkyl esters ofthe carboxylic acid. The carboxylate esters are conveniently formed byesterifying any of the carboxylic acid moieties present on the molecule.Prodrugs can typically be prepared using well-known methods, such asthose described by Burger's Medicinal Chemistry and Drug Discovery6^(th) ed. (Donald J. Abraham ed., 2001, Wiley) and Design andApplication of Prodrugs (H. Bundgaard ed., 1985, Harwood AcademicPublishers Gmfh).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of aDihydropyrazino-Pyrazine Compound that is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecompound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. A typical stereomerically pure compoundcomprises greater than about 80% by weight of one stereoisomer of thecompound and less than about 20% by weight of other stereoisomers of thecompound, greater than about 90% by weight of one stereoisomer of thecompound and less than about 10% by weight of the other stereoisomers ofthe compound, greater than about 95% by weight of one stereoisomer ofthe compound and less than about 5% by weight of the other stereoisomersof the compound, or greater than about 97% by weight of one stereoisomerof the compound and less than about 3% by weight of the otherstereoisomers of the compound. The Dihydropyrazino-Pyrazine Compoundscan have chiral centers and can occur as racemates, individualenantiomers or diastereomers, and mixtures thereof. All such isomericforms are included within the embodiments disclosed herein, includingmixtures thereof. The use of stereomerically pure forms of suchDihydropyrazino-Pyrazine Compounds, as well as the use of mixtures ofthose forms are encompassed by the embodiments disclosed herein. Forexample, mixtures comprising equal or unequal amounts of the enantiomersof a particular Dihydropyrazino-Pyrazine Compound may be used in methodsand compositions disclosed herein. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, S. H., Tablesof Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

It should also be noted the Dihydropyrazino-Pyrazine Compounds caninclude E and Z isomers, or a mixture thereof, and cis and trans isomersor a mixture thereof. In certain embodiments, theDihydropyrazino-Pyrazine Compounds are isolated as either the cis ortrans isomer. In other embodiments, the Dihydropyrazino-PyrazineCompounds are a mixture of the cis and trans isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of the Dihydropyrazino-Pyrazine Compounds are within the scopeof the present invention.

It should also be noted the Dihydropyrazino-Pyrazine Compounds cancontain unnatural proportions of atomic isotopes at one or more of theatoms. For example, the compounds may be radiolabeled with radioactiveisotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) sulfur-35(³⁵S), or carbon-14 (¹⁴C), or may be isotopically enriched, such as withdeuterium (²H), carbon-13 (¹³C), or nitrogen-15 (¹⁵N). As used herein,an “isotopologue” is an isotopically enriched compound. The term“isotopically enriched” refers to an atom having an isotopic compositionother than the natural isotopic composition of that atom. “Isotopicallyenriched” may also refer to a compound containing at least one atomhaving an isotopic composition other than the natural isotopiccomposition of that atom. The term “isotopic composition” refers to theamount of each isotope present for a given atom. Radiolabeled andisotopically enriched compounds are useful as therapeutic agents, e.g.,cancer and inflammation therapeutic agents, research reagents, e.g.,binding assay reagents, and diagnostic agents, e.g., in vivo imagingagents. All isotopic variations of the Dihydropyrazino-PyrazineCompounds as described herein, whether radioactive or not, are intendedto be encompassed within the scope of the embodiments provided herein.In some embodiments, there are provided isotopologues of theDihydropyrazino-Pyrazine Compounds, for example, the isotopologues aredeuterium, carbon-13, or nitrogen-15 enriched Dihydropyrazino-PyrazineCompounds.

It should be noted that if there is a discrepancy between a depictedstructure and a name for that structure, the depicted structure is to beaccorded more weight.

“Treating” as used herein, means an alleviation, in whole or in part, ofa cancer or a symptom associated with a cancer, or slowing, or haltingof further progression or worsening of those symptoms.

“Preventing” as used herein, means the prevention of the onset,recurrence or spread, in whole or in part, of a cancer, or a symptomthereof.

The term “effective amount” in connection with anDihydropyrazino-Pyrazine Compound or an androgen receptor antagonistmeans an amount alone or in combination capable of alleviating, in wholeor in part, a symptom associated with a cancer, or slowing or haltingfurther progression or worsening of those symptoms, or treating orpreventing a cancer in a subject having or at risk for having a cancer.The effective amount of the Dihydropyrazino-Pyrazine Compound or anandrogen receptor antagonist, for example in a pharmaceuticalcomposition, may be at a level that will exercise the desired effect;for example, about 0.005 mg/kg of a subject's body weight to about 100mg/kg of a patient's body weight in unit dosage for both oral andparenteral administration.

The term “cancer” refers to any of various malignant neoplasmscharacterized by the proliferation of cells that can invade surroundingtissue and metastasize to new body sites. Both benign and malignanttumors are classified according to the type of tissue in which they arefound. For example, fibromas are neoplasms of fibrous connective tissue,and melanomas are abnormal growths of pigment (melanin) cells. Malignanttumors originating from epithelial tissue, e.g., in skin, bronchi, andstomach, are termed carcinomas. Malignancies of epithelial glandulartissue such as are found in the breast, prostate, and colon, are knownas adenocarcinomas. Malignant growths of connective tissue, e.g.,muscle, cartilage, lymph tissue, and bone, are called sarcomas.Lymphomas and leukemias are malignancies arising among white bloodcells. Through the process of metastasis, tumor cell migration to otherareas of the body establishes neoplasms in areas away from the site ofinitial appearance. Bone tissues are one of the most favored sites ofmetastases of malignant tumors, occurring in about 30% of all cancercases. Among malignant tumors, cancers of the lung, breast, prostate orthe like are particularly known to be likely to metastasize to bone.

In the context of neoplasm, cancer, tumor growth or tumor cell growth,inhibition may be assessed by delayed appearance of primary or secondarytumors, slowed development of primary or secondary tumors, decreasedoccurrence of primary or secondary tumors, slowed or decreased severityof secondary effects of disease, arrested tumor growth and regression oftumors, among others. In the extreme, complete inhibition, is referredto herein as prevention or chemoprevention. In this context, the term“prevention” includes either preventing the onset of clinically evidentneoplasia altogether or preventing the onset of a preclinically evidentstage of neoplasia in individuals at risk. Also intended to beencompassed by this definition is the prevention of transformation intomalignant cells or to arrest or reverse the progression of premalignantcells to malignant cells. This includes prophylactic treatment of thoseat risk of developing the neoplasia.

As used herein, and unless otherwise specified, the term “in combinationwith” includes the administration of two or more therapeutic agentssimultaneously, concurrently, or sequentially within no specific timelimits unless otherwise indicated. In one embodiment, aDihydropyrazino-Pyrazine Compound is administered in combination with anandrogen receptor antagonist. In one embodiment, the agents are presentin the cell or in the subject's body at the same time or exert theirbiological or therapeutic effect at the same time. In one embodiment,the therapeutic agents are in the same composition or unit dosage form.In other embodiments, the therapeutic agents are in separatecompositions or unit dosage forms. In certain embodiments, a first agentcan be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a second therapeutic agent, orany combination thereof. For example, in one embodiment, the first agentcan be administered prior to the second therapeutic agent, for e.g. 1week. In another, the first agent can be administered prior to (forexample 1 day prior) and then concomitant with the second therapeuticagent.

The terms “patient” and “subject” as used herein include an animal,including, but not limited to, an animal such as a cow, monkey, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig, in one embodiment a mammal, in another embodiment a human.In one embodiment, a “patient” or “subject” is a human having a cancer.In one embodiment, the patient” or “subject” is a human havingmetastatic castration-resistant prostate cancer who has previouslyreceived docetaxel.

In the context of a cancer, inhibition may be assessed by inhibition ofdisease progression, inhibition of tumor growth, reduction of primarytumor, relief of tumor-related symptoms, inhibition of tumor secretedfactors (including tumor secreted hormones, such as those thatcontribute to carcinoid syndrome), delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, increased Time To Progression (TTP), increasedProgression Free Survival (PFS), increased Overall Survival (OS), amongothers. OS as used herein means the time from randomization until deathfrom any cause, and is measured in the intent-to-treat population. TTPas used herein means the time from randomization until objective tumorprogression; TTP does not include deaths. As used herein, PFS means thetime from randomization until objective tumor progression or death. Inone embodiment, PFS rates will be computed using the Kaplan-Meierestimates. In the extreme, complete inhibition, is referred to herein asprevention or chemoprevention. In this context, the term “prevention”includes either preventing the onset of clinically evident advancedcancer altogether or preventing the onset of a preclinically evidentstage of a cancer. Also intended to be encompassed by this definition isthe prevention of transformation into malignant cells or to arrest orreverse the progression of premalignant cells to malignant cells. Thisincludes prophylactic treatment of those at risk of developing a cancer.

In certain embodiments, the treatment of a cancer may be assessed byResponse Evaluation Criteria in Solid Tumors (RECIST 1.1) (see ThereasseP., et al. New Guidelines to Evaluate the Response to Treatment in SolidTumors. J. of the National Cancer Institute; 2000; (92) 205-216 andEisenhauer E. A., Therasse P., Bogaerts J., et al. New responseevaluation criteria in solid tumours: Revised RECIST guideline (version1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for allpossible combinations of tumor responses in target and non-targetlesions with our without the appearance of new lesions are as follows:

Target lesions Non-target lesions New lesions Overall response CR CR NoCR CR Incomplete No PR response/SD PR Non-PD No PR SD Non-PD No SD PDAny Yes or no PD Any PD Yes or no PD Any Any Yes PD CR = completeresponse; PR = partial response; SD = stable disease; and PD =progressive disease.

With respect to the evaluation of target lesions, complete response (CR)is the disappearance of all target lesions, partial response (PR) is atleast a 30% decrease in the sum of the longest diameter of targetlesions, taking as reference the baseline sum longest diameter,progressive disease (PD) is at least a 20% increase in the sum of thelongest diameter of target lesions, taking as reference the smallest sumlongest diameter recorded since the treatment started or the appearanceof one or more new lesions and stable disease (SD) is neither sufficientshrinkage to qualify for partial response nor sufficient increase toqualify for progressive disease, taking as reference the smallest sumlongest diameter since the treatment started.

With respect to the evaluation of non-target lesions, complete response(CR) is the disappearance of all non-target lesions and normalization oftumor marker level; incomplete response/stable disease (SD) is thepersistence of one or more non-target lesion(s) and/or the maintenanceof tumor marker level above the normal limits, and progressive disease(PD) is the appearance of one or more new lesions and/or unequivocalprogression of existing non-target lesions.

In certain embodiments, treatment of a cancer may be assessed by theinhibition of phosphorylation of S6RP, 4E-BP1, AKT and/or DNA-PK incirculating blood and/or tumor cells, and/or skin biopsies or tumorbiopsies/aspirates, before, during and/or after treatment with aDihydropyrazino-Pyrazine Compound. For example, the inhibition ofphosphorylation of S6RP, 4E-BP1, AKT and/or DNA-PK is assessed inB-cells, T-cells and/or monocytes. In other embodiments, treatment of acancer may be assessed by the inhibition of DNA-dependent protein kinase(DNA-PK) activity in skin samples and/or tumor biopsies/aspirates, suchas by assessment of the amount of pDNA-PK 52056 as a biomarker for DNAdamage pathways, before, during, and/or after Dihydropyrazino-PyrazineCompound treatment. In one embodiment, the skin sample is irradiated byUV light.

In the extreme, complete inhibition, is referred to herein as preventionor chemoprevention. In this context, the term “prevention” includeseither preventing the onset of clinically evident cancer altogether orpreventing the onset of a preclinically evident stage of a cancer. Alsointended to be encompassed by this definition is the prevention oftransformation into malignant cells or to arrest or reverse theprogression of premalignant cells to malignant cells. This includesprophylactic treatment of those at risk of developing a cancer.

5.2 Dihydropyrazino-Pyrazine Compounds

The compounds provided herein are generally referred to as“Dihydropyrazino-Pyrazine Compound(s).”

In one embodiment, the Dihydropyrazino-Pyrazine Compounds includecompounds having the following formula (I):

and pharmaceutically acceptable salts, clathrates, solvates,stereoisomers, tautomers, metabolites, isotopologues and prodrugsthereof, wherein:

R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstitutedheterocyclylalkyl;

R² is H, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aralkyl, or substituted or unsubstituted cycloalkylalkyl;

R³ is H, or a substituted or unsubstituted C₁₋₈ alkyl,

wherein in certain embodiments, the Dihydropyrazino-Pyrazine Compoundsdo not include7-(4-hydroxyphenyl)-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,depicted below:

In some embodiments of compounds of formula (I), R¹ is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridyl,1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl, orpyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl(for example, methyl), substituted or unsubstituted heterocyclyl (forexample, a substituted or unsubstituted triazolyl or pyrazolyl),aminocarbonyl, halogen (for example, fluorine), cyano, hydroxyalkyl andhydroxy. In other embodiments, R¹ is pyridyl substituted with one ormore substituents independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl (for example, methyl),substituted or unsubstituted heterocyclyl (for example, a substituted orunsubstituted triazolyl), halogen, aminocarbonyl, cyano, hydroxyalkyl(for example, hydroxypropyl), —OR, and —NR₂, wherein each R isindependently H, or a substituted or unsubstituted C₁₋₄ alkyl. In someembodiments, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In some embodiments, R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently a substituted or unsubstituted C₁₋₄ alkyl (for example,methyl), halogen (for example, fluoro), cyano, —OR, or —NR₂; m is 0-3;and n is 0-3. It will be understood by those skilled in the art that anyof the substituents R′ may be attached to any suitable atom of any ofthe rings in the fused ring systems.

In some embodiments of compounds of formula (I), R¹ is

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl; R′ is at each occurrence independently asubstituted or unsubstituted C₁₋₄ alkyl, halogen, cyano, —OR or —NR₂; mis 0-3; and n is 0-3.

In some embodiments of compounds of formula (I), R² is H, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedC₁₋₄ alkyl-heterocyclyl, substituted or unsubstituted C₁₋₄ alkyl-aryl,or substituted or unsubstituted C₁₋₄ alkyl-cycloalkyl. For example, R²is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl,tetrahydrofuranyl, tetrahydropyranyl, (C₁₋₄ alkyl)-phenyl, (C₁₋₄alkyl)-cyclopropyl, (C₁₋₄ alkyl)-cyclobutyl, (C₁₋₄ alkyl)-cyclopentyl,(C₁₋₄ alkyl)-cyclohexyl, (C₁₋₄ alkyl)-pyrrolidyl, (C₁₋₄alkyl)-piperidyl, (C₁₋₄ alkyl)-piperazinyl, (C₁₋₄ alkyl)-morpholinyl,(C₁₋₄ alkyl)-tetrahydrofuranyl, or (C₁₋₄ alkyl)-tetrahydropyranyl, eachoptionally substituted.

In other embodiments, R² is H, C₁₋₄ alkyl, (C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₄ alkyl (for example, methyl); R′ is at each occurrenceindependently H, —OR, cyano, or a substituted or unsubstituted C₁₋₄alkyl (for example, methyl); and p is 0-3.

In other embodiments of compounds of formula (I), R² is H, C₁₋₄ alkyl,(C₁₋₄alkyl)(OR),

wherein R is at each occurrence independently H, or a substituted orunsubstituted C₁₋₂ alkyl; R′ is at each occurrence independently H, —OR,cyano, or a substituted or unsubstituted C₁₋₂ alkyl; and p is 0-1.

In other embodiments of compounds of formula (I), R³ is H.

In some such embodiments described herein, R¹ is substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Forexample, R¹ is phenyl, pyridyl, pyrimidyl, benzimidazolyl,1H-pyrrolo[2,3-b]pyridyl, indazolyl, indolyl, 1H-imidazo[4,5-b]pyridine,pyridyl, 1H-imidazo[4,5-b]pyridin-2(3H)-onyl, 3H-imidazo[4,5-b]pyridyl,or pyrazolyl, each optionally substituted. In some embodiments, R¹ isphenyl substituted with one or more substituents independently selectedfrom the group consisting of substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted heterocyclyl, aminocarbonyl, halogen,cyano, hydroxyalkyl and hydroxy. In others, R¹ is pyridyl substitutedwith one or more substituents independently selected from the groupconsisting of C₁₋₈ alkyl, substituted or unsubstituted heterocyclyl,halogen, aminocarbonyl, cyano, hydroxyalkyl, —OR, and —NR₂, wherein eachR is independently H, or a substituted or unsubstituted C₁₋₄ alkyl. Instill others, R¹ is 1H-pyrrolo[2,3-b]pyridyl or benzimidazolyl,optionally substituted with one or more substituents independentlyselected from the group consisting of substituted or unsubstituted C₁₋₈alkyl, and —NR₂, wherein R is independently H, or a substituted orunsubstituted C₁₋₄ alkyl.

In certain embodiments, the compounds of formula (I) have an R¹ groupset forth herein and an R² group set forth herein.

In some embodiments of compounds of formula (I), the compound inhibitsTOR kinase. In other embodiments of compounds of formula (I), thecompound inhibits DNA-PK. In certain embodiments of compounds of formula(I), the compound inhibits both TOR kinase and DNA-PK.

In some embodiments of compounds of formula (I), the compound at aconcentration of 10 μM inhibits TOR kinase, DNA-PK, PI3K, or acombination thereof by at least about 50%. Compounds of formula (I) maybe shown to be inhibitors of the kinases above in any suitable assaysystem.

Representative Dihydropyrazino-Pyrazine Compounds of formula (I) includecompounds from Table A.

Table A.

-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[3,2-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-benzo[d]imidazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(cis-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-((trans-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((cis-4-hydroxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(trans-4-hydroxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(5-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-hydroxypyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   5-(8-isopropyl-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-indazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-aminopyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(methyl    amino)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-hydroxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-pyrazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-4-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyrimidin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-methoxypyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(1H-indazol-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(pyridin-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-aminopyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-methyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   2-(2-hydroxypropan-2-yl)-5-(8-(trans-4-methoxy    cyclohexyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)pyridine    1-oxide;-   4-methyl-5-(7-oxo-8-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)picolinamide;-   5-(8-((cis-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   7-(1H-pyrazol-4-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-((7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1(2H)-yl)methyl)benzonitrile;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   3-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   5-(8-((trans-4-methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide;-   3-((7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-2-oxo-3,4-dihydropyrazino[2,3-b]pyrazin-1    (2H)-yl)methyl)benzonitrile;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3R)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1S,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R,3S)-3-methoxycyclopentyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-morpholinoethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-isopropyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-imidazo[4,5-b]pyridin-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((cis-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cis-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   4-(7-oxo-8-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)benzamide;-   7-(1H-indazol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3R)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1R,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((1S,3S)-3-methoxycyclopentyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-5-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(1H-indol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-((trans-4-methoxycyclohexyl)methyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((cis-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-benzyl-7-(2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(trans-4-methoxycyclohexyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(5-fluoro-2-methyl-4-(4H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(3-fluoro-2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(2-methoxyethyl)-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans-4-methoxycyclohexyl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(cyclopentylmethyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(1-hydroxyethyl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(2-hydroxypropan-2-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(4-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-(trifluoromethyl)benzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(3-methoxypropyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-methyl-2-(methylamino)-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (R)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   (S)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,3-dimethyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-amino-4-methyl-1H-benzo[d]imidazol-6-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(2-methyl-4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   7-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;-   1-(1-hydroxypropan-2-yl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one;    and-   1-(2-hydroxyethyl)-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,    and pharmaceutically acceptable salts, clathrates, solvates,    stereoisomers, tautomers, metabolites, isotopologues and prodrugs    thereof.

5.3 Methods for Making Dihydropyrazino-Pyrazine Compounds

The Dihydropyrazino-Pyrazine Compounds can be obtained via standard,well-known synthetic methodology, see e.g., March, J. Advanced OrganicChemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. Startingmaterials useful for preparing compounds of formula (III) andintermediates therefore, are commercially available or can be preparedfrom commercially available materials using known synthetic methods andreagents.

Particular methods for preparing compounds of formula (I) are disclosedin U.S. Pat. No. 8,110,578, issued Feb. 7, 2012, and U.S. Pat. No.8,569,494, issued Oct. 29, 2013, each incorporated by reference hereinin their entirety.

5.4 Androgen Receptor Antagonists

In one embodiment, the androgen receptor antagonist is enzalutamide(marketed as Xtandi®, Astellas Pharma US, Inc.), also known as andreferred to herein as MDV3100, having the chemical name4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamideand the structure:

5.5 Methods of Use

Provided herein are methods for treating or preventing a cancercomprising administering an effective amount of aDihydropyrazino-Pyrazine Compound and an effective amount of an androgenreceptor antagonist to a patient having a cancer.

In certain embodiments, the cancer is prostate cancer.

In other embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is a relapsed or refractory solid tumor. Inone embodiment, the cancer is metastatic. In another, the cancer ishormone refractory. In yet another, the cancer is an E-twenty six (ETS)overexpressing cancer.

In one embodiment, the solid tumor is an advanced solid tumor.

In another embodiment, the cancer is E-twenty six (ETS) overexpressingcastration-resistant prostate cancer.

In other embodiments, the cancer is a cancer associated with thepathways involving mTOR, PI3K, or Akt kinases and mutants or isoformsthereof. Other cancers within the scope of the methods provided hereininclude those associated with the pathways of the following kinases:PI3Kα, PI3Kβ, PI3Kδ, KDR, GSK3α, GSK3β, ATM, ATX, ATR, cFMS, and/orDNA-PK kinases and mutants or isoforms thereof. In some embodiments, thecancers associated with mTOR/PI3K/Akt pathways include solid tumors, forexample, prostate cancer.

In other embodiments, the cancer is metastatic castration-resistantprostate cancer.

In other embodiments, the cancer is breast cancer.

In certain embodiments, provided herein are methods for achieving aResponse Evaluation Criteria in Solid Tumors (for example, RECIST 1.1)of complete response, partial response or stable disease in a patienthaving a solid tumor, comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist to said patient In certain embodiments, providedherein are methods for achieving a Prostate Cancer Working Group 2(PCWG2) Criteria of complete response, partial response or stabledisease in a patient having prostate cancer, comprising administering aneffective amount of a Dihydropyrazino-Pyrazine Compound in combinationwith an androgen receptor antagonist to said patient

In certain embodiments, provided herein are methods for increasingsurvival without tumor progression of a patient having a cancer,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to said patient.

In one embodiment, provided herein are methods for preventing ordelaying a Response Evaluation Criteria in Solid Tumors (for example,RECIST 1.1) of progressive disease in a patient, comprisingadministering an effective amount of a Dihydropyrazino-Pyrazine Compoundin combination with an effective amount of an androgen receptorantagonist to a patient having a cancer. In one embodiment theprevention or delaying of progressive disease is characterized orachieved by a change in overall size of the target lesions, of forexample, between −30% and +20% compared to pre-treatment. In anotherembodiment, the change in size of the target lesions is a reduction inoverall size of more than 30%, for example, more than 50% reduction intarget lesion size compared to pre-treatment. In another, the preventionis characterized or achieved by a reduction in size or a delay inprogression of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by a reductionin the number of target lesions compared to pre-treatment. In another,the prevention is achieved or characterized by a reduction in the numberor quality of non-target lesions compared to pre-treatment. In oneembodiment, the prevention is achieved or characterized by the absenceor the disappearance of target lesions compared to pre-treatment. Inanother, the prevention is achieved or characterized by the absence orthe disappearance of non-target lesions compared to pre-treatment. Inanother embodiment, the prevention is achieved or characterized by theprevention of new lesions compared to pre-treatment. In yet anotherembodiment, the prevention is achieved or characterized by theprevention of clinical signs or symptoms of disease progression comparedto pre-treatment, such as cancer-related cachexia or increased pain.

In certain embodiments, provided herein are methods for decreasing thesize of target lesions in a patient compared to pre-treatment,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer.

In certain embodiments, provided herein are methods for decreasing thesize of a non-target lesion in a patient compared to pre-treatment,comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer.

In certain embodiments, provided herein are methods for achieving areduction in the number of target lesions in a patient compared topre-treatment, comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer.

In certain embodiments, provided herein are methods for achieving areduction in the number of non-target lesions in a patient compared topre-treatment, comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer.

In certain embodiments, provided herein are methods for achieving anabsence of all target lesions in a patient, comprising administering aneffective amount of a Dihydropyrazino-Pyrazine Compound in combinationwith an effective amount of an androgen receptor antagonist to a patienthaving a cancer.

In certain embodiments, provided herein are methods for achieving anabsence of all non-target lesions in a patient, comprising administeringan effective amount of a Dihydropyrazino-Pyrazine Compound incombination with an effective amount of an androgen receptor antagonistto a patient having a cancer.

In certain embodiments, provided herein are methods for treating acancer, the methods comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer,wherein the treatment results in a complete response, partial responseor stable disease, as determined by Response Evaluation Criteria inSolid Tumors (for example, RECIST 1.1).

In certain embodiments, provided herein are methods for treating acancer, the methods comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer,wherein the treatment results in a reduction in target lesion size, areduction in non-target lesion size and/or the absence of new targetand/or non-target lesions, compared to pre-treatment.

In certain embodiments, provided herein are methods for treating acancer, the methods comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer,wherein the treatment results in prevention or retarding of clinicalprogression, such as cancer-related cachexia or increased pain.

In some embodiments, provided herein are methods for treating a cancer,the methods comprising administering an effective amount of aDihydropyrazino-Pyrazine Compound in combination with an effectiveamount of an androgen receptor antagonist to a patient having a cancer,wherein the treatment results in one or more of inhibition of diseaseprogression, inhibition of tumor growth, reduction of primary tumor,relief of tumor-related symptoms, inhibition of tumor secreted factors(including tumor secreted hormones, such as those that contribute tocarcinoid syndrome), delayed appearance of primary or secondary tumors,slowed development of primary or secondary tumors, decreased occurrenceof primary or secondary tumors, slowed or decreased severity ofsecondary effects of disease, arrested tumor growth and regression oftumors, increased Time To Progression (TTP), increased Progression FreeSurvival (PFS), and/or increased Overall Survival (OS), among others.

In some embodiments, the Dihydropyrazino-Pyrazine Compound is a compoundas described herein. In one embodiment, the Dihydropyrazino-PyrazineCompound is a compound of formula (I). In one embodiment, theDihydropyrazino-Pyrazine Compound is a compound from Table A. In oneembodiment, the Dihydropyrazino-Pyrazine Compound is Compound 1 (aDihydropyrazino-Pyrazine Compound set forth herein having molecularformula C₂₁H₂₇N₅O₃). In one embodiment, the Dihydropyrazino-PyrazineCompound is Compound 2 (a Dihydropyrazino-Pyrazine Compound set forthherein having molecular formula C₁₆H₁₆N₈O). In one embodiment, theDihydropyrazino-Pyrazine Compound is Compound 3 (aDihydropyrazino-Pyrazine Compound set forth herein having molecularformula C₂₀H₂₅N₅O₃). In one embodiment, Compound 1 is7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one,alternatively named7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1R*,4R*)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In another embodiment, Compound 2 is1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or a tautomer thereof, for example,1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,or1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In another embodiment, Compound 3 is1-((trans)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one,alternatively named1-((1r,4r)-4-hydroxycyclohexyl)-7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one.In one embodiment, Compound 3 is a metabolite of Compound 1.

In one embodiment, the androgen receptor antagonist is MDV-3100.

A Dihydropyrazino-Pyrazine Compound administered in combination with anandrogen receptor antagonist can be further combined with radiationtherapy or surgery. In certain embodiments, a Dihydropyrazino-PyrazineCompound is administered in combination with an androgen receptorantagonist to patient who is undergoing radiation therapy, haspreviously undergone radiation therapy or will be undergoing radiationtherapy. In certain embodiments, a Dihydropyrazino-Pyrazine Compound isadministered in combination with an androgen receptor antagonist to apatient who has undergone surgery, such as tumor removal surgery.

Further provided herein are methods for treating patients who have beenpreviously treated for a cancer, as well as those who have notpreviously been treated. Further provided herein are methods fortreating patients who have undergone surgery in an attempt to treat acancer, as well as those who have not. Because patients with a cancerhave heterogenous clinical manifestations and varying clinical outcomes,the treatment given to a patient may vary, depending on his/herprognosis. The skilled clinician will be able to readily determinewithout undue experimentation specific secondary agents, types ofsurgery, and types of non-drug based standard therapy that can beeffectively used to treat an individual patient with a cancer.

In certain embodiments, a Dihydropyrazino-Pyrazine Compound isadministered in combination with an androgen receptor antagonist to apatient in cycles. Cycling therapy involves the administration of anactive agent(s) for a period of time, followed by a rest for a period oftime, and repeating this sequential administration. Cycling therapy canreduce the development of resistance, avoid or reduce the side effects,and/or improves the efficacy of the treatment.

In one embodiment, a Dihydropyrazino-Pyrazine Compound is administeredin combination with an androgen receptor antagonist daily in single ordivided doses for about 3 days, about 5 days, about one week, about twoweeks, about three weeks, about four weeks (e.g., 28 days), about fiveweeks, about six weeks, about seven weeks, about eight weeks, about tenweeks, about fifteen weeks, or about twenty weeks, followed by a restperiod of about 1 day to about ten weeks. In one embodiment, the methodsprovided herein contemplate cycling treatments of about one week, abouttwo weeks, about three weeks, about four weeks, about five weeks, aboutsix weeks, about eight weeks, about ten weeks, about fifteen weeks, orabout twenty weeks. In some embodiments, a Dihydropyrazino-PyrazineCompound is administered in combination with an androgen receptorantagonist in single or divided doses for about 3 days, about 5 days,about one week, about two weeks, about three weeks, about four weeks(e.g., 28 days), about five weeks, or about six weeks with a rest periodof about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 29, or 30 days. In some embodiments, the rest period is 1 day. Insome embodiments, the rest period is 3 days. In some embodiments, therest period is 7 days. In some embodiments, the rest period is 14 days.In some embodiments, the rest period is 28 days. The frequency, numberand length of dosing cycles can be increased or decreased.

In one embodiment, the methods provided herein comprise: i)administering to the subject a first daily dose of aDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist; ii) optionally resting for a period of at least oneday where an androgen receptor antagonist is not administered to thesubject; iii) administering a second dose of a Dihydropyrazino-PyrazineCompound in combination with an androgen receptor antagonist to thesubject; and iv) repeating steps ii) to iii) a plurality of times.

In one embodiment, the methods provided herein comprise administering tothe subject a dose of an androgen receptor antagonist on day 1, followedby administering a Dihydropyrazino-Pyrazine Compound in combination withan androgen receptor antagonist to the subject on day 2 and subsequentdays.

In certain embodiments, a Dihydropyrazino-Pyrazine Compound incombination with an androgen receptor antagonist is administeredcontinuously for between about 1 and about 52 weeks. In certainembodiments, a Dihydropyrazino-Pyrazine Compound in combination with anandrogen receptor antagonist is administered continuously for about 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In certain embodiments,a Dihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist is administered continuously for about 7, about 14,about 21, about 28, about 35, about 42, about 84, or about 112 days.

In certain embodiments, when a Dihydropyrazino-Pyrazine Compound isadministered in combination with an androgen receptor antagonist theDihydropyrazino-Pyrazine Compound is administered at an amount of about2.5 mg to about 50 mg per day (such as about 0.5 mg, 1 mg, 2 mg, 4 mg, 8mg, 10 mg, 15 mg, 16 mg, 20 mg, 25 mg, 30 mg, 45 mg, 60 mg, 90 mg, 120mg or 128 mg per day) and an androgen receptor antagonist isadministered at an amount of about 50 mg to about 200 mg per day (suchas about 80 mg, about 120 mg or about 160 mg per day). In certainembodiments, about 2.5 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 10 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 15 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 16 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 20 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 25 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 30 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, about 45 mg per day of a Dihydropyrazino-Pyrazine Compoundis administered in combination with about 80 mg, about 120 mg or about160 mg per day of an androgen receptor antagonist. In certainembodiments, when an androgen receptor antagonist is administered incombination with a Dihydropyrazino-Pyrazine Compound, the androgenreceptor antagonist is administered as four discrete capsules. Forexample, when a dose of 160 mg per day of an androgen receptorantagonist is administered in combination with aDihydropyrazino-Pyrazine Compound, it can be administered as four 40 mgcapsules. A Dihydropyrazino-Pyrazine Compound and an androgen receptorantagonist can each be independently administered once (QD), twice (BD),three times (TID) or four times per day.

In certain embodiments, when a Dihydropyrazino-Pyrazine Compound isadministered in combination with an androgen receptor antagonist, theDihydropyrazino-Pyrazine Compound:androgen receptor antagonist ratio isfrom about 1:1 to about 1:10. In certain embodiments, when aDihydropyrazino-Pyrazine Compound is administered in combination with anandrogen receptor antagonist, the Dihydropyrazino-PyrazineCompound:androgen receptor antagonist ratio is less than about 1:1, lessthan about 1:3 or less than about 1:10. In certain embodiments, when aDihydropyrazino-Pyrazine Compound is administered in combination with anandrogen receptor antagonist, the Dihydropyrazino-PyrazineCompound:androgen receptor antagonist ratio is about 1:1, about 1:3 orabout 1:10.

In certain embodiments, when a Dihydropyrazino-Pyrazine Compound isadministered in combination with an androgen receptor antagonist, theDihydropyrazino-Pyrazine Compound:androgen receptor antagonist ratio isfrom about 1:1 to about 1:30. In certain embodiments, when aDihydropyrazino-Pyrazine Compound is administered in combination with anandrogen receptor antagonist, the Dihydropyrazino-PyrazineCompound:androgen receptor antagonist ratio is less than about 1:1, lessthan about 1:10 or less than about 1:30. In certain embodiments, when aDihydropyrazino-Pyrazine Compound is administered in combination with anandrogen receptor antagonist, the Dihydropyrazino-PyrazineCompound:androgen receptor antagonist ratio is about 1:1, about 1:10 orabout 1:30.

5.6 Pharmaceutical Compositions and Routes of Administration

Provided herein are compositions comprising an effective amount of aDihydropyrazino-Pyrazine Compound and an effective amount of an androgenreceptor antagonist and compositions, comprising an effective amount ofa Dihydropyrazino-Pyrazine Compound and an androgen receptor antagonistand a pharmaceutically acceptable carrier or vehicle.

In some embodiments, the pharmaceutical compositions described hereinare suitable for oral, parenteral, mucosal, transdermal or topicaladministration.

The compositions can be administered to a patient orally or parenterallyin the conventional form of preparations, such as capsules,microcapsules, tablets, granules, powder, troches, pills, suppositories,injections, suspensions and syrups. Suitable formulations can beprepared by methods commonly employed using conventional, organic orinorganic additives, such as an excipient (e.g., sucrose, starch,mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphateor calcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g, sodium benzoate, sodium bisulfate,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax(e.g., cocoa butter, white petrolatum or polyethylene glycol). Theeffective amount of the Dihydropyrazino-Pyrazine Compound in thepharmaceutical composition may be at a level that will exercise thedesired effect; for example, about 0.005 mg/kg of a patient's bodyweight to about 10 mg/kg of a patient's body weight in unit dosage forboth oral and parenteral administration.

The dose of a Dihydropyrazino-Pyrazine Compound and the dose of anandrogen receptor antagonist to be administered to a patient is ratherwidely variable and can be subject to the judgment of a health-carepractitioner. In general, the Dihydropyrazino-Pyrazine Compounds and anandrogen receptor antagonist can be administered one to four times a dayin a dose of about 0.005 mg/kg of a patient's body weight to about 10mg/kg of a patient's body weight in a patient, but the above dosage maybe properly varied depending on the age, body weight and medicalcondition of the patient and the type of administration. In oneembodiment, the dose is about 0.01 mg/kg of a patient's body weight toabout 5 mg/kg of a patient's body weight, about 0.05 mg/kg of apatient's body weight to about 1 mg/kg of a patient's body weight, about0.1 mg/kg of a patient's body weight to about 0.75 mg/kg of a patient'sbody weight or about 0.25 mg/kg of a patient's body weight to about 0.5mg/kg of a patient's body weight. In one embodiment, one dose is givenper day. In any given case, the amount of the Dihydropyrazino-PyrazineCompound administered will depend on such factors as the solubility ofthe active component, the formulation used and the route ofadministration.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and about 2000 mg, about 1 mg and about 200mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about250 mg and about 1000 mg, about 500 mg and about 1000 mg, about 1 mg toabout 30 mg, about 1 mg to about 25 mg or about 2.5 mg to about 20 mg ofa Dihydropyrazino-Pyrazine Compound alone or in combination with anandrogen receptor antagonist. In another embodiment, provided herein areunit dosage formulations that comprise 1 mg, 2.5 mg, 5 mg, 7.5 mg, 8 mg,10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 45 mg, 50 mg, 70 mg, 100 mg, 125 mg,140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg,750 mg, 1000 mg or 1400 mg of a Dihydropyrazino-Pyrazine Compound aloneor in combination with an androgen receptor antagonist. In anotherembodiment, provided herein are unit dosage formulations that compriseabout 2.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg orabout 45 mg of a Dihydropyrazino-Pyrazine Compound alone or incombination with an androgen receptor antagonist. In a particularembodiment, provided herein are unit dosage formulations that compriseabout 5 mg, about 7.5 mg and about 10 mg of a Dihydropyrazino-PyrazineCompound alone or in combination with an androgen receptor antagonist.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 10 mg, about 15 mg, about 30 mg, about 45 mg, about 50mg, about 75 mg, about 100 mg or about 400 mg of aDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 20 mg to about 60 mg of an androgen receptor antagonistin combination with a Dihydropyrazino-Pyrazine Compound. In a particularembodiment, provided herein are unit dosage formulations comprisingabout 40 mg of an androgen receptor antagonist in combination with aDihydropyrazino-Pyrazine Compound.

In certain embodiments, provided herein are unit dosage formulationswherein the Dihydropyrazino-Pyrazine Compound:androgen receptorantagonist ratio is from about 1:1 to about 1:10. In certainembodiments, provided herein are unit dosage formulations wherein theDihydropyrazino-Pyrazine Compound:androgen receptor antagonist ratio isless than about 1:1, less than about 1:3 or less than about 1:10. Incertain embodiments, provided herein are unit dosage formulationswherein the Dihydropyrazino-Pyrazine Compound:androgen receptorantagonist ratio is about 1:1, about 1:3 or about 1:10.

A Dihydropyrazino-Pyrazine Compound can be administered in combinationwith an androgen receptor antagonist once, twice, three, four or moretimes daily.

A Dihydropyrazino-Pyrazine Compound can be administered in combinationwith an androgen receptor antagonist orally for reasons of convenience.In one embodiment, when administered orally, a Dihydropyrazino-PyrazineCompound in combination with an androgen receptor antagonist isadministered with a meal and water. In another embodiment, theDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist is dispersed in water or juice (e.g., apple juice ororange juice) and administered orally as a suspension. In anotherembodiment, when administered orally, a Dihydropyrazino-PyrazineCompound in combination with an androgen receptor antagonist isadministered in a fasted state.

The Dihydropyrazino-Pyrazine Compound can also be administered incombination with an androgen receptor antagonist intravenously, such asintravenous infusion, or subcutaneously, such as subcutaneous injection.The mode of administration is left to the discretion of the health-carepractitioner, and can depend in-part upon the site of the medicalcondition.

In one embodiment, provided herein are capsules containing aDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist without an additional carrier, excipient or vehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a Dihydropyrazino-Pyrazine Compound, an effectiveamount of an androgen receptor antagonist, and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories andsuspensions and the like. Compositions can be formulated to contain adaily dose, or a convenient fraction of a daily dose, in a dosage unit,which may be a single tablet or capsule or convenient volume of aliquid. In one embodiment, the solutions are prepared from water-solublesalts, such as the hydrochloride salt. In general, all of thecompositions are prepared according to known methods in pharmaceuticalchemistry. Capsules can be prepared by mixing a Dihydropyrazino-PyrazineCompound with a suitable carrier or diluent and filling the properamount of the mixture in capsules. The usual carriers and diluentsinclude, but are not limited to, inert powdered substances such asstarch of many different kinds, powdered cellulose, especiallycrystalline and microcrystalline cellulose, sugars such as fructose,mannitol and sucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. In one embodiment, the pharmaceutical composition islactose-free. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.Illustrative tablet formulations comprising Compound 2 are providedherein.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a Dihydropyrazino-Pyrazine Compound incombination with an androgen receptor antagonist as a suppository,typical bases can be used. Cocoa butter is a traditional suppositorybase, which can be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the Dihydropyrazino-Pyrazine Compound in combination withan androgen receptor antagonist can be delayed or prolonged by properformulation. For example, a slowly soluble pellet of theDihydropyrazino-Pyrazine Compound in combination with an androgenreceptor antagonist can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the Dihydropyrazino-Pyrazine Compound incombination with an androgen receptor antagonist in oily or emulsifiedvehicles that allow it to disperse slowly in the serum.

In certain embodiments, the Dihydropyrazino-Pyrazine Compound isadministered in a formulation set forth in U.S. Patent ApplicationPublication No. 2013-0142873, published Jun. 6, 2013, which isincorporated herein in its entirety (see particularly paragraph [0323]to paragraph [0424], and paragraph [0636] to paragraph [0655]). In otherembodiments, the Dihydropyrazino-Pyrazine Compound is administered in aformulation set forth in U.S. Provisional Patent Application No.61/828,506, filed May 29, 2013, which is incorporated herein in itsentirety (see particularly paragraph [0246] to paragraph [0403], andparagraph [0571] to paragraph [0586]).

In certain embodiments, the Dihydropyrazino-Pyrazine Compound isadministered in a formulation set forth in U.S. Provisional ApplicationNo. 61/813,064, filed Apr. 17, 2013, which is incorporated herein in itsentirety (see particularly paragraph [0168] to paragraph [0189] andparagraph [0262] to paragraph [0294]). In other embodiments, theDihydropyrazino-Pyrazine Compound is administered in a formulation setforth in U.S. Provisional Patent Application No. 61/911,201, filed Dec.3, 2013, which is incorporated herein in its entirety (see particularlyparagraph [0170] to paragraph [0190], and paragraph [0264] to paragraph[0296]).

5.7 Kits

In certain embodiments, provided herein are kits comprising aDihydropyrazino-Pyrazine Compound and an androgen receptor antagonist.

In certain embodiments, provided herein are kits comprising one or moreunit dosage forms of a Dihydropyrazino-Pyrazine Compound, such as thosedescribed herein, and one or more unit dosage forms of an androgenreceptor antagonist, such as those described herein.

In certain embodiments, the kits provided herein further compriseinstructions for use, such as for administering aDihydropyrazino-Pyrazine Compound and an androgen receptor antagonist.

6. EXAMPLES 6.1 Biochemical Assays

mTOR HTR-FRET Assay.

The following is an example of an assay that can be used to determinethe TOR kinase inhibitory activity of a test compound.Dihydropyrazino-Pyrazine Compounds were dissolved in DMSO and preparedas 10 mM stocks and diluted appropriately for the experiments. Reagentswere prepared as follows:

“Simple TOR buffer” (used to dilute high glycerol TOR fraction): 10 mMTris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen mTOR(cat#PV4753) was diluted in this buffer to an assay concentration of0.200 μg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl₂, 50 mM Hepes, pH7.4, 50 mM β-GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5μg/mL GST-p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100,0.01% BSA, 0.1 mM EDTA, 12.7 μg/mL Cy5-αGST Amersham (Cat#PA92002V), 9ng/mL α-phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L),627 ng/mL α-mouse Lance Eu (Perkin Elmer Cat#AD0077).

To 20 μL of the Simple TOR buffer is added 0.5 μL of test compound inDMSO. To initiate the reaction 5 μL of ATP/Substrate solution was addedto 20 μL of the Simple TOR buffer solution (control) and to the compoundsolution prepared above. The assay was stopped after 60 min by adding 5μL of a 60 mM EDTA solution; 10 μL of detection reagent solution wasthen added and the mixture was allowed to sit for at least 2 hoursbefore reading on a Perkin-Elmer Envision Microplate Reader set todetect LANCE Eu TR-FRET (excitation at 320 nm and emission at 495/520nm).

Dihydropyrazino-Pyrazine Compounds were tested in the mTOR HTR-FRETassay and were found to have activity therein, with certain compoundshaving an IC₅₀ below 10 μM in the assay, with some compounds having anIC₅₀ between and 0.005 nM and 250 nM, others having an IC₅₀ between and250 nM and 500 nM, others having an IC₅₀ between 500 nM and 1 μM, andothers having an IC₅₀ between 1 μM and 10 μM.

DNA-PK Assay.

DNA-PK assay is performed using the procedures supplied in the PromegaDNA-PK assay kit (catalog # V7870). DNA-PK enzyme can be purchased fromPromega (Promega cat#V5811).

Selected Dihydropyrazino-Pyrazine Compounds as described herein have, orare expected to have, an IC₅₀ below 10 μM in this assay, with someDihydropyrazino-Pyrazine Compounds as described herein having an IC₅₀below 1 μM, and others having an IC₅₀ below 0.10 μM.

6.2 Cell Based Assays

Apoptosis Induction.

Increasing concentrations of compound (Compound 2 and/or MDV3100: 30 μM)were spotted via an acoustic dispenser (EDC ATS-100) into an empty384-well plate in a 10-point serial dilution fashion (3-fold dilution)in duplicate within the plate. Cells (LNCaP, PC3 or VCAP) were thendirectly seeded at desired densities to the compound-spotted 384-wellplates. Cells were cultured for 48 hours at 37° C./5% CO₂ and wereassessed via Caspase 3/7-Glo (Promega) and read for luminescence.Results are shown in FIGS. 3B, C and D for LNCAP, and in FIG. 3E forVCAP, wherein Compound 2 and MDV3100 combination treatmentsynergistically induces apoptosis.

6.3 In Vivo Assays

ETS-Positive Prostate Cancer Xenograft Model.

Results are shown in FIGS. 1 and 2.

LNCap-HR Tumor Model.

A xenograft study was conducted with castration resistant LNCaP(LNCaP-HR) tumor-bearing mice. Castration resistant LNCaP-HR tumors weredeveloped by several cycles of serial transplantation and in vivopassaging of parental LNCaP tumor cells in castrated SCID (severecombined immunodeficiency) mice. For xenograft studies, tumor-bearinganimals were generated by injecting precisely determined numbers ofcells or precise size of tumor fragments subcutaneously in the flankregion above the right hind leg into castrated SCID mice. Followinginoculation of animals, the tumors were allowed to grow to a certainsize prior to randomization. The mice bearing LNCaP-HR xenograft tumorsranging between 200 and 600 mm³ were pooled together and randomized intovarious treatment groups. A typical efficacy study design involvedadministering one or more compounds at various dose levels totumor-bearing mice. Additionally, reference chemotherapeutic agents(positive control) and negative controls were similarly administered andmaintained. Routes of administration can include intraperitoneal (IP) ororal (PO). Tumor measurements and body weights were taken over thecourse of the study and morbidity and mortality were recorded. Necropsy,histopathology, western blots, MesoScale, immunohistochemistry and PCRcan also be performed to enhance understanding of disease and drugaction. For a typical xenograft study, SCID mice bearing LNCaP-HR tumorswere randomized and dosed with compounds ranging from, for example, 100mg/kg to 0.1 mg/kg with different dose scheduling, including, but notlimited to, qd, q2d, q3d, q5d, q7d and bid. In certain studies acombination of two or more agents were dosed simultaneously. Thecompounds were formulated in various types of formulation. Some of theformulations included CMC-Tween (0.5% CMC/0.25% Tween), NPS(n-methylpyrrolidone, PEG, Saline), DMSO-CMC-Tween (1% CMC, 0.1% Tween80 and 5% dimethyl sulfoxide in water) and were delivered orally orintraperitonially. The mice were dosed for 2-4 weeks. Tumors weremeasured twice a week using calipers and tumor volumes were calculatedusing the formula of W²×L/2. Statistical analysis was performed using aone-way analysis of variance (ANOVA) followed by Dunnett's post-hoccomparison with the vehicle-treated control group.

The xenograft study was conducted with castration resistant LNCaP-HRtumor-bearing mice. Castrated male SCID mice were inoculatedsubcutaneously with LNCaP-HR cells in the flank region above the righthind leg. Following inoculation of animals, the tumors were allowed togrow to about 325 mm³ prior to randomization. On Day 26 following tumorcell inoculation, the mice bearing LNCaP-HR tumors ranging between 98and 530 mm³ were pooled together and randomized into various treatmentgroups. Compound 2 was formulated in 0.5% CMC and 0.25% Tween 80 inwater (as a suspension). The animals were orally administered vehicle(CMC-Tween) or Compound 2 once daily (QD) for up to 15 days. Doses ofCompound 2 ranged between 1 and 5 mg/kg. The positive control MDV-3100(50 mg/kg, Q4D) was administered via oral route. MDV-3100 was formulatedin 1% CMC, 0.1% Tween 80 and 5% dimethyl sulfoxide (DMSO) in water (as asuspension). Tumors were measured twice a week using calipers and tumorvolumes were calculated using the formula of W²×L/2. Statisticalanalysis was performed using a one-way analysis of variance (ANOVA)followed by Dunnett's post-hoc comparison with the vehicle-treatedcontrol group. Results are shown in FIG. 4.

6.4 Compound Formulations

Illustrative formulations of Compound 1 useful in the methods providedherein are set forth in Tables 1-4, below.

TABLE 1 Amounts Ingredients mg % w/w Compound 1 20.0 15.38 Lactosemonohydrate, NF (Fast Flo 316) 63.98 49.22 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry yellow 03K12429 5.2 4.0

TABLE 2 Amounts Ingredients mg % w/w Compound 1 5.0 3.80 Lactosemonohydrate, NF (Fast Flo 316) 78.98 60.70 Microcrystalline cellulose,NF (Avicel pH 102) 40.30 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)3.90 3.00 Stearic acid, NF 0.52 0.40 Magnesium Stearate, NF 1.30 1.00Total 130.0 100 Opadry II pink 85F94211 5.2 4% weight gain

TABLE 3 Amounts Ingredients mg % w/w Compound 1 15.0 20.0 30.0 15.38Lactose monohydrate, NF (Fast Flo 48.37 64.50 96.75 49.62 316)Microcrystalline cellulose, NF 30.23 40.30 60.45 31.00 (Avicel pH 112)Croscarmellose sodium, NF (Ac- 2.925 3.90 5.85 3.00 Di-Sol) MagnesiumStearate, NF 0.975 1.30 1.95 1.00 Total 97.50 130.0 195.00 100 Opadryyellow 03K12429 3.9 4.0 Opadry II Pink 85F94211 5.2 4.0 Opadry Pink03K140004 7.8 4.0

TABLE 4 Amounts Ingredients mg % w/w Compound 1 45.00 15.38 Lactosemonohydrate, NF (Fast Flo 316) 143.955 49.22 Microcrystalline cellulose,NF (Avicel pH 102) 90.675 31.00 Croscarmellose sodium, NF (Ac-Di-Sol)8.775 3.00 Stearic acid, NF 1.170 0.40 Magnesium Stearate, NF 2.925 1.00Total 292.50 100 Opadry pink 03K140004 11.70 4.0

Illustrative formulations of Compound 2 useful in the methods providedherein are set forth in Table 5, below.

TABLE 5 Exemplary Tablet Formulations % w/w (mg) Batch # 1 2 3 4Ingredients Compound 2 (active ingredient) 10 10 10 10 Mannitol(Mannogem EZ) qs qs qs qs Microcrystalline Cellulose 25 25 25 25 (PH112) Sodium Starch Glycolate 3 3 3 3 Silicon dioxide 1 1 1 1 Stearicacid 0.5 0.5 0.5 0.5 Disodium EDTA 0.5 0.5 BHT 0.4 0.4 MagnesiumStearate 0.65 0.65 0.65 0.65 Total 100 100 100 100 Color Yellow YellowYellow Yellow

A number of references have been cited, the disclosures of which areincorporated herein by reference in their entirety. The embodimentsdisclosed herein are not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the disclosed embodiments and anyembodiments that are functionally equivalent are encompassed by thepresent disclosure. Indeed, various modifications of the embodimentsdisclosed herein are in addition to those shown and described hereinwill become apparent to those skilled in the art and are intended tofall within the scope of the appended claims.

What is claimed is:
 1. A method for achieving complete response, partial response or stable disease, as determined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), in a patient having castration-resistant prostate cancer, comprising administering to a patient having castration-resistant prostate cancer an effective amount of a Dihydropyrazino-Pyrazine Compound in combination with an effective amount of MDV3100, wherein the Dihydropyrazino-Pyrazine Compound is a compound having the structure:

or a pharmaceutically acceptable salt, clathrate, solvate, stereoisomer, tautomer or isotopologue thereof.
 2. The method of claim 1, wherein the castration-resistant prostate cancer is a relapsed or refractory castration-resistant prostate cancer.
 3. The method of claim 1, wherein the castration-resistant prostate cancer is an E-twenty six (ETS) overexpressing castration-resistant prostate cancer.
 4. The method of claim 1, wherein the castration-resistant prostate cancer is metastatic castration-resistant prostate cancer.
 5. The method of claim 1, wherein the Dihydropyrazino-Pyrazine Compound is administrated in a unit dosage formulation comprising about 5 mg, about 7.5 mg or about 10 mg of the Dihydropyrazino-Pyrazine Compound in combination with an effective amount of MDV3100.
 6. The method of claim 5, wherein the Dihydropyrazino-Pyrazine Compound is administrated in a unit dosage formulation comprising about 7.5 mg of the Dihydropyrazino-Pyrazine Compound in combination with an effective amount of MDV3100.
 7. The method of claim 6, wherein the Dihydropyrazino-Pyrazine Compound is administrated in the unit dosage formulation twice a day in combination with an effective amount of MDV3100.
 8. The method of claim 1, wherein MDV3100 is administrated in a unit dosage formulation comprising about 160 mg of MDV3100 in combination with an effective amount of the Dihydropyrazino-Pyrazine Compound.
 9. The method of claim 8, wherein MDV3100 is administrated in the unit dosage formulation once a day in combination with an effective amount of the Dihydropyrazino-Pyrazine Compound. 